Chapter 9 - New treatments in development

Key points

  • Practical and perceived drawbacks of warfarin are limiting its potential to prevent stroke
  • alternative anticoagulants in development aim to offer efficacy, safety and convenience, without need for monitoring or dose adjustment
  • Three oral anticoagulants are in the final stages of development for the prevention of stroke in AF
  • Promising minimally-invasive procedures have also been developed for correcting abnormal heart rhythms and eliminating the source of AF-related blood clots

Limitations of warfarin and aspirin restrict their use and effectiveness in the prevention of stroke in patients with AF. These limitations have led to an ongoing search for alternative effective and convenient therapies. In addition, there have been developments in anti- arrhythmic drugs used to treat AF. These developments are discussed in more detail below.

Anticoagulant agents

There are many challenges involved in the effective use of current anticoagulants to prevent stroke. Taken together, they point clearly to what might be the ideal characteristics of an anticoagulant for long-term use in AF.165

  • As effective as warfarin
  • A large therapeutic window (a wide separation between blood levels that reduce the risk of a blood clot and those that substantially increase the risk of bleeding)
  • A good safety profile in a wide range of patients, including the elderly
  • A low tendency to interact with food and other drugs
  • No need for regular monitoring and dose adjustment
  • Easy and simple to take (i.e., by mouth in pill or capsule form on daily basis)

Warfarin can be very effective, is relatively simple to take, and is somewhat safer than many physicians appear to believe, but it does not fulfil the remaining criteria for an ideal anticoagulant. Warfarin interacts with food and other drugs in a way that can lead to blood levels far outside a very narrow therapeutic window. Consequently, warfarin requires frequent monitoring and dose adjustments. When monitoring and adjustment are lax, both the effectiveness and safety of warfarin are compromised.

Understandably, there has been a long search for alternative anticoagulants. The clotting process is a complicated cascade of biological reactions providing many potential targets for a new drug. Yet it has taken decades of research to uncover new compounds that are effective in tackling some of these targets. The agents that are most advanced in their development act on single proteins in the coagulation pathway; either clotting factor Xa (pronounced ‘Ten A’) which is involved in the amplification of the clotting response, or on thrombin which enables the final step of the clotting process to take place.165 Today, development of a handful of new oral anticoagulants has advanced to human trials in large numbers of patients.

The below table summarises the new anticoagulation agents which have filed, or which plan imminently to file, applications for European regulatory approval. These and other agents in the final stage of development are discussed below.

New anticoagulant agents offer potential alternative to warfarin in some patientsc

Agent Commercial Name Class Current indications

Status of AF indication

Rivaroxaban Xarelto Direct factor Xa inhibitor

VTEa
AFb

Licenced 2011
Apixaban Eliquis Direct factor Xa inhibitor VTEa Filed 2011
Dabigatran Pradaxa Direct thrombin inhibitor

VTEa
AFb

Licenced 2011

a The prevention of venous thromboembolism in adults after hip or knee replacement
b To prevent strokes and the formation of clots in adults who have an abnormal heart beat called ‘non-valvular atrial fibrillation’ and are considered to be at risk of stroke

c Accurate at Feb-12

Oral factor Xa inhibitors

Clotting factor Xa has few functions in the body outside coagulation, making it an excellent target for potential new anticoagulants as this may result in fewer side effects.166 Inhibition of factor Xa inhibits thrombin generation, while allowing existing thrombin to continue its vital role in blood clotting.166 Oral inhibitors of factor Xa in late-stage development include rivaroxaban, apixaban and edoxaban. Two factor Xa inhibitors are currently licensed in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA); rivaroxaban,170 and apixaban.167 Both are available Europe-wide following authorisation from the European Medicines Agency. Both agents are available for the prevention of clotting problems in the veins in adults after hip or knee replacement surgery. For this indication, called venous thromboembolism (VTE), rivaroxaban is taken orally, once daily at a fixed dose; apixaban is taken orally, twice daily at a fixed dose.

Unlike warfarin, rivaroxaban and apixaban have a wide therapeutic window and do not require routine monitoring. The manufactures of rivaroxaban have also now submitted additional indications for licence, including stroke prevention in patients with AF and the treatment of deep vein thrombosis. The manufacturers of apixaban have announced plans to make regulatory filings in 2011 for stroke prevention in AF patients.

Rivaroxaban

The pivotal clinical study of rivaroxaban is called ROCKET AF.168 169 The results of the study showed that AF patients taking rivaroxaban had a comparable risk of stroke and a similar risk of bleeding compared to patients taking warfarin.169

ROCKET-AF was a randomised, double-blind study that compared the efficacy and safety of rivaroxaban 20 mg once daily with warfarin for the prevention of stroke in approximately 14,000 high-stroke-risk patients with AF.168 169

Apixaban

Two pivotal studies of apixaban have recently released results. The AVERROES study compared apixaban with aspirin in 5,599 AF patients who were unable to take warfarin. The study was stopped early having demonstrated clearly that apixaban was associated with a significant reduction in strokes when compared with aspirin. A second pivotal trial, ARISTOTLE, compared apixaban with warfarin in over 18,000 AF patients. Results from this trial show that apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

Edoxaban

Pivotal studies of edoxaban have yet to complete but earlier trials indicated that AF patients taking edoxaban had a similar incidence of bleeding to those assigned to warfarin.172 A pivotal phase III study (ENGAGE- AF TIMI 48) is underway to demonstrate the safety and efficacy profile of different edoxaban doses compared to warfarin.171

Indirect factor Xa inhibitors

Another group of factor Xa inhibitors are under investigation. These agents, instead of acting directly, limit the activity of factor Xa via antithrombin. Among these indirect factor Xa inhibitors, biotinylated idraparinux is the most studied and the only example to have been involved in a late-stage clinical study. Unlike the direct Factor Xa inhibitors above, biotinylated idraparinux is administered by subcutaneous injection.165 A study called BOREALIS-AF was evaluating whether subcutaneous biotinylated idraparinux administered once a week was at least as effective as warfarin for the prevention of stroke in patients with AF.171 However, the trial was halted by the sponsor. This is the second trial of biotinylated idraparinux to have been stopped early. However, unlike a predecessor BOREALIS-AF was not stopped because of a safety concern. This earlier trial, which used a different formulation of the drug, was stopped as a result of bleeding concerns.

Thrombin inhibitors

Dabigatran

Dabigatran etexilate directly inhibits the action of thrombin, blocking the final step of the clotting cascade which converts fibrinogen to fibrin. Similar to apixaban and rivaroxaban, throughout Europe dabigatran has been approved for the prevention of VTE in adults after total hip replacement or total knee replacement surgery.173 The pivotal, late-stage clinical study of dabigatran is called RE-LY, which compared the efficacy and safety of dabigatran with warfarin in 18,113 AF patients. RE-LY compared two doses of dabigatran, taken orally, twice daily, to warfarin. The lower dose was associated with a stroke rate comparable to that seen with warfarin, but with a lower rate of major bleeds. The higher dose resulted in a significantly lower rate of stroke compared to warfarin and a similar rate of major bleeds.174 Further studies of dabigatran and other direct thrombin inhibitors are ongoing.176 55

Antiplatelet agents

Clopidogrel is an inhibitor of platelet aggregation. Reduced platelet aggregation reduces the risk of a blood clot forming. In a study called ACTIVE-A, clopidogrel in combination with aspirin was compared to aspirin alone for the prevention of stroke in AF patients for whom warfarin therapy was unsuitable. While clopidogrel in combination with aspirin significantly reduced the risk of stroke in patients with AF, it was also associated with a significantly greater rate of major bleeding 177

Additional studies are under way to assess the efficacy and safety of clopidogrel for stroke prevention in patients with AF. 171 Clopidogrel is currently licensed for other indications including the prevention of atherothrombotic events in patients suffering from heart attack. 185

Alternative strategies

Current strategies are focused on drugs that target the process of clot formation. However, other strategies are emerging for patients with AF. These include:178

  • Drugs and procedures that target AF itself
  • Drugs and procedures to control heart rhythm and heart rate
  • Drugs and procedures to prevent blood clots reaching the brain

New rate and rhythm control drugs

In rhythm control, drugs are used to restore and maintain the sinus rhythm of the heart; in rate control, drugs are used to maintain a suitably low heart rate. Examples of drugs used for rhythm or rate control include amiodarone, digoxin and β-blockers.

Dronedarone is a new anti-arrhythmic drug licensed for use in clinically stable patients with non-permanent atrial fibrillation, to prevent recurrence of AF or to lower the pulse rate. In trials dronedarone has been shown to reduce the incidence of death or hospitalisation due to cardiovascular events compared with placebo. 188

Non-pharmacological methods

Non-pharmacological interventions for stroke prevention in AF concentrate on eliminating the AF itself; stopping potentially harmful blood clots from reaching the brain, or by preventing the formation of clots.

Non-pharmacological management of abnormal heart rhythm

There are numerous non-pharmacological methods for the management of abnormal heart rhythm. 178 These include:

  • Electrical cardioversion: the process by which an abnormally fast heart rate or disturbance in heart rhythm is terminated by the delivery of an electric current to the heart at a specific moment in the heart cycle
  • Radiofrequency (RF) catheter ablation: a minimally-invasive procedure used to correct a faulty electrical pathway in the heart
  • Non-RF ablation: open surgical or minimally-invasive procedures that correct the faulty electrical pathways from the heart
  • Left atrial appendage (LAA) occlusion: minimally-invasive procedure that either prevents clots from forming or prevents them from leaving the site of formation in the heart

Current data suggest that catheter ablation is more effective than anti- arrhythmic drug therapy in maintaining normal heart rhythm. 179 Whether or not this intervention affects the incidence strokes requires further evaluation in clinical trials.

Procedural interventions to reduce stroke risk

One procedural approach to preventing stroke in AF patients seeks to remove an anatomical contributor to clot formation. More than 90% of blood clots in AF patients form in the left atrial appendage (LAA) of the heart. 178 The LAA is a small sac behind an opening the wall of the left atrium. It has been suggested that AF particularly degrades the normal flow of blood in the LAA, allowing clot formation.

Sealing the left atrial appendage, isolating it from the main atrial chamber, may therefore prove to be an effective and permanent way to reduce the risk of blood clots and stroke. Several new occlusion devices have been developed that block the LAA. Such devices are designed to be placed permanently, sealing the opening of the LAA. Once in place, potentially harmful blood clots no longer have opportunity to form in the LAA and any thrombotic material in the LAA is prevented from entering the bloodstream and causing stroke. 180 181 One of these devices, Watchman, recently received approval for use in Europe. 181 The results of a recently published trial, PROTECT-AF, showed that closure of the LAA with Watchman was comparable to warfarin for stroke prevention. The study authors noted caution, having observed an overall increase in the rate of adverse events in the LAA group compared to warfarin. However, unlike drugs, device-related interventions frequently demonstrate substantial safety improvements associated with increased operator experience. A subsequent paper from an extension of the same study investigated this effect. A significant reduction in safety events was observed during the second half of the study period compared to the first. It was also noted that the impact of these safety events, as defined by significant disability or death, was statistically superior in the Watchman group compared with the warfarin group. The authors concluded that closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with AF. 182 183

Summary

To summarise, there are several pharmacological agents in development for use in patients with AF, including the new oral anticoagulants rivaroxaban, dabigatran and apixaban. Minimally-invasive device interventions for the management of arrhythmias and the reduction of stroke risk are also being developed.

Valuable insights into the impact of these new therapies on the prevention of stroke in patients with AF can be gained from real-life registries. A number of registries of AF patients are in existence, most of which are country specific or focused on North America.

A new global registry has now been established, the Global Anticoagulant Registry in the FIELD (GARFIELD). GARFIELD will prospectively follow 50,000 newly-diagnosed AF patients and 5,000 patients with previously-diagnosed AF, over 6 years. 192 Patients will be included and followed, regardless of whether or not they receive appropriate therapy. The GARFIELD registry will document details such as the risk factors, treatment patterns and clinical events associated with AF, and will provide a picture of the real-life global burden of the condition. It is also hoped that GARFIELD will show how the new advances in therapy can contribute to the prevention of stroke in patients with AF. 186

It is hoped that the availability of new therapy options, together with a greater understanding of their impact on the burden of stroke, will pave the way for better management of patients with AF.